Cerebral infarction and myocardial infarction, representative ischemic diseases, are caused by necrosis of the surrounding tissues that is also caused by clogging of cerebral or coronary arteries by thrombus, which was already narrowed by various factors such as hypertension, hyperlipidemia, diabetes, or smoking etc.
Cardiovascular disease, the leading cause of death worldwide each year, comprises approximately 30% of the total death, of which cerebral and myocardial infarction occupies 75%. Therefore, those two diseases and cancer are representative three diseases with the highest morbidity. The methods to decrease the morbidity caused by myocardial infarction and cerebral infarction are classified into two groups: one is to prevent vascular occlusion by treating hypertension and hyperlipidemia, and the other is to reduce necrosis of surrounding tissues when vascular occlusion occurs.
The best way to reduce necrotic region is to reperfuse the occluded arteries as soon as possible, for which thrombolytic agents have been used to dissolve thrombus or embolus, and subsequently, to reperfuse the occluded arteries. However, even reperfusion by the thrombolytic agents will not be effective in preventing infarction once tissues of heart and brain become necrotized after 3˜6 hours of occlusion. In reality, the prompt reperfusion is difficult since patients can not reach the hospital within 3˜6 hours after the occlusion. Furthermore, the already-damaged heart and brain do not regenerate well. Therefore, preventing the tissue damage until occluded arteries are reperfused at the hospital is another way to increase therapeutic efficacy, for which antiapoptotic agents can be an option because one cause of the cell death in cerebral and myocardial infarction is apoptosis (Crow M T et al., Circ. Res., 95(10), pp 957-970, 2004; Friedlander R M, N. Engl. J. Med., 348(14), pp 1365-1375, 2003.
Also, the damages of transplanted tissues resulting from kidney transplant (Daemen M A et al., Transplantation, 73(11), pp 1693-1700, 2002) and the plastic surgery (Gastman B R et al., P; Ast. Reconstr. Surg., 111, pp 1481-1496, 2003) are induced by the apoptosis following an ischemia-reperfusion.
Additionally, the myocardiac injury can occur where the amount of oxygen required is more excessive than that of oxygen supplied by a pump-oxygenator, or subsequent cerebral injury can also occur by hypotension when a surgery is performed with cardiac arrest. For example, the heart failure caused by myocardial injury and the hemiplegia caused by brain damage may occur when the operations accompany with the occlusion of the part of blood vessels, for example, coronary artery bypass graft performed in case of the obstruction of coronary artery, and aneurysm surgery performed where the aneurysm occurs in cerebral arteries and aorta, etc. Actually, during the operative or interventional therapy for aortic aneurysm, side effects, such as ischemic heart disease, renal failure, paraplegia etc., occur in 3-16% of the patients. Accordingly, those side effects could be reduced if antiapoptotic agents are given before the operation.
The cause of apoptotic neuronal cell death has not been clarified well, however, there have been reported that apoptotic neuronal cell death is caused by decrease of ATP concentration and occurrence of edema, which occurs in case that transient ischemia following the blockage of oxygen and glucose supply to the brain is generated. It has been reported that apoptotic neuronal cell death in cerebral ischemia is induced by two mechanisms: one is excitatory neuronal cell death mechanism, whereby cerebral ischemia induces excessive accumulation of glutamate outside cells, influx of the glutamate into the cells, and excessive accumulation of calcium ion inside the cells (Kang T C et al., J. Neurocytol., 30(12), pp 945-955, 2001), the other is oxidative neuronal cell death mechanism, whereby increase of free radicals, generated by sudden oxygen supply at ischemia-reperfusion induces damages to DNA and cytoplasm (Won M H et al., Brain Res., 836(1-2), pp 70-78, 1999). Based on these kinds of mechanistic studies, there has been endeavor to screen inhibitors of apoptotic neuronal cell death or the mechanism thereof up to date. However, the effective inhibitors of apoptotic neuronal cell death has been not yet found.
It has been reported that minocycline, a tetracycline antibiotic which inhibits apoptosis under ischemic condition, has efficacy in treating ischemic diseases, such as cerebral infarction (Yrjanheikki J et al., Proc. Natl. Acad. Sci. USA, 96(23), pp 13496-13500, 1999), myocardial infarction (Scarabelli T M et al., J. Am. Coll. Cardiol., 43(5), pp 865-874, 2004), ischemic acute renal failure (Wang J et al., J. Biol. Chem., 279(19), pp 19948-19954, 2004), as well as degenerative brain diseases caused by neuronal cell apoptosis, such as Alzheimer's disease (Hunter C L, Eur. J. Neurosci., 19(12), pp 3305-3316, 2004), Parkinson's disease (Wu D C et al., J. Neurosci., 22(5), pp 1763-1771, 2002), amyotrophic lateral sclerosis (Zhu S et al., Nature, 417(6884), pp 74-78, 2002), Huntington's disease (Chen. M. et al., Nat. Med., 6(7), pp 797-801, 2000) and spinal cord injury (Teng Y D et al., Proc. Natl. Acad. Sci. USA, 101(9), pp 3071-3076, 2004). The inventors of the present invention also confirmed that tetracyclines improved cell viability under similar ischemic conditions used in the present study (Korean Patent Registration No. 0404134; U.S. Pat. Nos. 6,716,822 & 6,818,625). In addition, other antibiotics such as aminoglycosides, quinolones also improved cell survival under ischemic condition, and G418 (geneticin), one of the aminoglycosides, in particular, showed efficacy in treating myocardial infarction (U.S. Pat. No. 6,716,822). In the subsequent experiments, G418 inhibited apoptosis under ischemic conditions and showed efficacy in treating cerebral infarction as well. Based on these results, it has been expected that any samples showing the same cell survival effect under ischemic condition as that of G418 may have efficacy in treating ischemic diseases such as myocardial infarction, and also have efficacy in preventing and treating degenerative brain diseases that are caused by apoptosis. Through screening, the present inventors finally found that the crude extract of Gramineae plant, including Triticum aestivum L., improved cell viability under hypoxic conditions, and subsequently showed that the crude extract had efficacy in treating ischemic diseases such as cerebral and myocardial infarction, and degenerative brain diseases such as Alzheimer's disease, which was proven using ischemic and degenerative brain diseases animal models (Korea Patent Registration No. 10-0723950; and PCT/KR2006/000027).
The seeds of representative plants belonging to family Gramineae have been reported to contain about 10% moisture, carbohydrate component including 50-60% starch (25% in case of barley), 10-20% protein, 2-8% lipid, and 10-20% total dietary fiber (40% in case of barley) including 1-3% soluble dietary fiber (9% in case of barley) (Ranhotra G S et al., Cereal Chemistry 68(5), pp 556-558, 1991); or to contain 50-60% starch, 10-20% protein, 1-5% lipid, and 10-20% total dietary fiber (Grausgruber H et al., In Genetic variation for plant breeding (Vollmann J et al. (Eds.)), pp 23-26, Eucarpia & Boku, Vienna, 2004).
Arabinoxylan and beta-glucan are two major dietary fibers consisting of the cell wall of endosperm cell (Izydorczyk M S et al., Carbohydrate Polymers, 28, pp 33-48, 1995; Zekovic D B et al., Crit. Rev. Biotech., 25, pp 205-230, 2005), whereby the cell wall of wheat (Triticum aestivum L.) (Philippe S et al., Planta, 224(2), pp 449-461, 2006) and rye (Secale cereale L.) (Vinkx C J A et al., J. Cereal Sci., 24, pp 1-14, 1996) has been reported to contain more arabinoxylan than beta-glucan while that of oat (Avena sativa L.) (Miller S S et al., Cereal Chem., 72(5), pp 421-427, 1995) and barley (Hordeum vulgare L.) (Kanauchi M and Bamforth C W, Cereal Chem., 78(2), pp 121-124, 2001) has been reported to contain more beta-glucan than arabinoxylan. Generally, arabinoxylan is composed of arabinose and xylose; beta-glucan is composed of glucose (Izydorczyk M S et al., Carbohydr. Polym., 28, pp 33-48, 1995).
In addition to polymers, such as arabinoxylan and beta-glucan, the cell wall also comprises compounds showing high antioxidative effect, i.e., ferulic acid participating in crosslinking arabinoxylan molecules (Adams E L et al., Carbohydr. Res., 340, pp 1841-1845, 2005), coumaric acid, vanillic acid, p-OH benzoic acid and syringic acid etc (Zhou K et al., J. Agric. Food Chem., 52, pp 6108-6114, 2004; Clifford M N, J. Sci. Food Agric., 79, pp 362-372, 1999).
Starch, a main reserve substance in the seed, root, stem, bulb, fruit etc of the green plants having abundant chlorophyll, is important as a carbohydrate source to higher animals. It is a colorless and odorless white powder having molecular weight ranging from 1,000,000 to 10,000,000, and having specific gravity of 1.65; exists as a granular form with different sizes and morphologies, depending on plants; and is a mixture of amylose and amylopectin with almost constant ratio in several kinds of starch, generally, 20-30% amylose and 70-80% amylopectin (Yoo et al., Carbohydr. Polymers, 49, pp 297-305, 2002). However, glutinous rice, waxy maize and etc., comprise little amylose and mainly amylopectin.
Although the inventors of the present inventions have reported that the crude extract of Gramineae plants, including wheat, improves cell viability under hypoxic conditions, and has an efficacy in improving and treating the ischemic diseases and degenerative brain diseases, using animal disease models (Korea Patent Registration No. 10-0723950; and PCT/KR2006/000027), there has been not disclosed that the purified starch, or total dietary fiber isolated from Gramineae plants and components of the dietary fiber, such as arabinoxylan, arabinose, xylose and beta-glucan, has an efficacy in improving and treating ischemic diseases and degenerative brain diseases in any of the above cited literatures, the disclosures of which are incorporated herein by reference.
Accordingly, the inventors of the present invention have completed the present inventions by investigating and confirming that starch or total dietary fiber isolated from Gramineae plants improved cell survival under hypoxic conditions, as well as in the presence of beta-amyloid or 6-hydroxydopamine, and that the starch or total dietary fiber also had an efficacy in improving and treating the ischemic diseases and degenerative brain diseases, using animal disease models.